Steven Zacks

Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response.

The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on‐treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha‐2a injection or peginterferon alpha‐2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2‐log drop and slow responders (SRs) with a less than 2‐log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon‐stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)‐inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN‐related genes and down‐regulation of genes involved in IFN inhibition and hepatic stellate cell activation. Conclusion: These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy. (HEPATOLOGY 2007.)

Race, insulin resistance and hepatic steatosis in chronic hepatitis C

Hepatic steatosis is common in chronic hepatitis C and has been linked to concurrent obesity, insulin resistance, diabetes, disease severity, and poor response to therapy. Racial differences in rates of obesity and diabetes may contribute to racial differences in hepatic steatosis and treatment response. The aim of the present study was to compare hepatic steatosis and its associations between African American (AA) and Caucasian American (CA) patients with chronic hepatitis C, genotype 1, participating in a prospective study of peginterferon and ribavirin therapy. Liver biopsy results were available from 194 AA patients and 205 CA patients. The 2 groups were compared for anthropometric, clinical, and biochemical features and insulin resistance estimated by the homeostasis model assessment index (HOMA‐IR). Sixty‐one percent of the AA patients and 65% of the CA patients had hepatic steatosis (P = 0.38). In univariable analysis, steatosis was associated with HOMA‐IR, body mass index, waist circumference, serum triglycerides, aminotransferase level, and histological scores for inflammation and fibrosis. After adjusting for these features, AA patients had a lower risk of steatosis than did CA patients (OR 0.54, 95% CI 0.32‐0.91, P = 0.02). Insulin resistance but not steatosis was associated with a lower rate of sustained virological response when adjusted for known factors that predict response (relative risk 0.87, 95% CI 0.77‐0.99, P = 0.028). Conclusion: After adjusting for the higher prevalence of features associated with hepatic steatosis, AA patients had a lower prevalence of hepatic steatosis than did CA patients with chronic hepatitis C, genotype 1. Insulin resistance but not steatosis was independently associated with lower sustained virological response. (HEPATOLOGY 2006;45:80–87.)

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

BACKGROUND & AIMS The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. METHODS In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. RESULTS Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. CONCLUSIONS Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Clinical risk factors for portopulmonary hypertension.

Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case‐control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes · second · cm−5, and pulmonary capillary wedge pressure ≤ 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right‐sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio = 2.90, 95% confidence interval 1.20‐7.01, P = 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio = 4.02, 95% confidence interval 1.14‐14.23, P = 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio = 0.24, 95% confidence interval 0.09‐0.65, P = 0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension. Conclusion: Female sex and autoimmune hepatitis were associated with an increased risk of portopulmonary hypertension, whereas hepatitis C infection was associated with a decreased risk in patients with advanced liver disease. Hormonal and immunologic factors may therefore be integral to the development of portopulmonary hypertension. (HEPATOLOGY 2008.)

Impact of Hepatopulmonary Syndrome on Quality of Life and Survival in Liver Transplant Candidates

BACKGROUND & AIMS Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension, but the impact on functional status, quality of life, and survival is poorly defined. We assessed the impact of HPS in patients evaluated for liver transplantation. METHODS We performed a prospective multicenter cohort study of patients being evaluated for liver transplantation in 7 academic centers in the United States. Patients with HPS (defined as an increased alveolar-arterial oxygen gradient with intrapulmonary vasodilation) were compared with those without HPS in terms of demographics and clinical variables. New York Heart Association functional class, quality of life, and survival were assessed. RESULTS Seventy-two patients with HPS and 146 patients without HPS were compared. There were no differences in age, sex, or etiology or severity of liver disease between the groups; however, patients with HPS were less likely to have a history of smoking (P = .03). Patients with HPS had worse New York Heart Association functional class (P = .005) and had significantly worse quality of life in certain domains compared with patients without HPS. In addition, patients with HPS also had a significantly increased risk of death compared with patients without HPS despite adjustment for age, sex, race/ethnicity, Model for End-Stage Liver Disease score, and liver transplantation (adjusted hazard ratio = 2.41; 95% confidence interval, 1.31-4.41; P = .005). CONCLUSIONS HPS was associated with a significant increase in risk of death as well as worse functional status and quality of life in patients evaluated for liver transplantation.

A population-based cohort study comparing laparoscopic cholecystectomy and open cholecystectomy

A population-based cohort study comparing laparoscopic cholecystectomy and open cholecystectomy

Genetic Risk Factors for Portopulmonary Hypertension in Patients with Advanced Liver Disease

RATIONALE Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood. OBJECTIVES To identify genetic risk factors for PPHTN in patients with advanced liver disease. METHODS We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dynes.s(-1).cm(-5), and pulmonary capillary wedge pressure < or =15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient. MEASUREMENTS AND MAIN RESULTS The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P < 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels. CONCLUSIONS Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.

Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis.

Hepatosteatosis is associated with increased expression of tumor necrosis factor alpha (TNF‐α) and interleukin (IL)‐12, major T helper (Th) 1 cytokines, and reduced hepatic natural killer T (NKT) cell numbers. The relationship between lipid accumulation, cytokine expression, and hepatic NKT cells is not known. This study was conducted to assess the role of IL‐12 in the development of hepatic steatosis and its potential impact on liver NKT cells. Male C57Bl/6 wildtype (WT) and IL‐12‐deficient (IL‐12−/−) mice were fed a choline‐deficient diet (CDD) for 0, 10, or 20 weeks. CDD led to marked hepatosteatosis, reduced hepatic but not splenic NKT cell numbers and function, and increased hepatic expression of the Th1‐type cytokines IL‐12, interferon gamma (IFN‐γ), and TNF‐α in WT mice. The absence of IL‐12 resulted in similar CDD‐induced hepatosteatosis, but preserved hepatic NKT cells and significantly reduced hepatic IFN‐γ and TNF‐α expression. Treatment of CDD‐fed mice with lipopolysaccharide led to a significant increase in hepatic IL‐12 expression, and Kupffer cell (KC) depletion reduced liver IL‐12 expression and restored NKT cells in CDD‐induced fatty liver. Interestingly, KCs from CDD‐fed mice failed to produce increased quantities of IL‐12 upon activation in vitro when compared to similarly treated KCs from control fed mice, suggesting that secondary factors in vivo promote heightened IL‐12 production. Finally, human livers with severe steatosis showed a substantial decrease in NKT cells. Conclusion: Hepatosteatosis reduces the numbers of hepatic NKT cells in a KC‐and IL‐12‐dependent manner. Our results suggest a pivotal and multifunctional role of KC‐derived IL‐12 in the altered immune response in steatotic liver, a process that is likely active within human nonalcoholic fatty liver disease. (HEPATOLOGY 2010;51:130–141.)

Isolated Donor Specific Alloantibody-Mediated Rejection after ABO Compatible Liver Transplantation

Antibody‐mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno‐transplantation, but its role after ABO compatible liver transplantation is controversial.

Social stigmatization and hepatitis C virus infection.

Goal Our aim was to assess stigmatization by evaluating the impact of hepatitis C virus (HCV) on social interactions, feelings of rejection, internalized shame, and financial insecurity, and behavior. Background HCV patients suffer from slowly progressive disease. Although much research has improved the long-term prognosis of chronic HCV, quality of life may be affected by perceived social stigmatization. Study In a cross-sectional study, HCV patients without cirrhosis or significant comorbidities were recruited from the University of North Carolina viral hepatitis clinic. Subjects completed a questionnaire administered by a trained interviewer that assessed changes in sexual behavior, personal hygiene habits, social function, and interactions. Additionally, subjects completed validated, standardized questionnaires, the Health Status Questionnaire, and the SCL-90-R. Frequencies were calculated for the prevalence of stigmatization and altered social interaction. Correlations between education and behavior changes were assessed. A series of multivariate analyses controlling for age, sex, and education were performed to assess the association between HCV acquisition risk and stigmatization. Results One hundred seventy-five of 217 potential subjects (81%) participated in the survey. The average age was 45.2±7.7 years. Fifty-five percent were men and 53% were single. Twenty-nine percent had some college education. Risk factors for HCV acquisition included transfusion (21%) and injection drug use (29%), whereas 32% had an unknown mode of infection. Among common activities, 47% were less likely to share drinking glasses, 14% were less likely to prepare food, and one-third of subjects were less likely to share a towel. Thirty-five percent of respondents reported changes in their sexual practices. Decreased frequency of kissing and sexual intercourse was reported in 20% and 27% of individuals, respectively. Almost half of the single subjects reported increased use of condoms compared with only 20% among married couples. The majority of subjects perceived financial insecurity, internalized shame, and social rejection. Only 39% reported health impairment. Education level did not influence behavior change. Conclusion The majority of HCV subjects alter common behaviors and report financial insecurity, internalized shame, and social rejection, regardless of the method of HCV acquisition or socioeconomic status. These findings indicate that all HCV individuals be counseled and encouraged to participate in educational programs at the time of diagnosis to reduce unnecessary behavioral changes and stigmatization perceptions to improve quality of life.